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Here, it is reported that drug\u2010cocktail core@shell nanocarriers are developed for the codelivery of lipophilic irinotecan (ITC) and the hydrophilic 5\u2010fluorouracil (5\u2010FU) metabolite (FdUMP), a commonly used combination in chemotherapy regimens for colorectal cancer. With a drug loading of 57% by mass, these nanocarriers achieve one of the highest reported drug payloads for a chemotherapeutic drug cocktail. Crucially, using a probe\u2010based imaging strategy with mechanistically responsive fluorescent reporters, we found\u00a0that after slow uptake predominantly via macropinocytosis, the nanocarriers rapidly traffic to endolysosomal compartments, where the acidic environment triggers sustained drug release. In alignment with the slow uptake and trafficking behavior, these nanocarriers induce a delayed yet prolonged cytotoxic effect in colorectal cancer cells. 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Together, this work highlights both the therapeutic potential of these nanocarriers and the broad applicability of the probe\u2010based imaging approach to elucidate the mechanistic intracellular trafficking and nuclear delivery of different types of nanoparticles delivering cargoes beyond cancer chemotherapy\u00a0in various cellular models.<\/jats:p>","DOI":"10.1002\/smsc.202500470","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:35:56Z","timestamp":1765805756000},"source":"Crossref","is-referenced-by-count":2,"title":["Macropinocytic Uptake and pH\u2010Responsive Endolysosomal Processing Drive Sustained Chemotherapeutic Efficacy of High\u2010Load Core@Shell Nanocarriers in Colorectal Cancer"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-1725","authenticated-orcid":false,"given":"Dolma","family":"Choezom","sequence":"first","affiliation":[{"name":"Translational Molecular Imaging, Clinic for 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